Meta-Analysis and Systematic Review of Coagulation Disbalances in COVID-19: 41 Studies and 17,601 Patients

  1. Polina Len
  2. Gaukhar Iskakova
  3. Zarina Sautbayeva
  4. Aigul Kussanova
  5. Ainur T. Tauekelova
  6. Madina M. Sugralimova
  7. Anar S. Dautbaeva
  8. Meruert M. Abdieva
  9. Eugene D. Ponomarev
  10. Alexander Tikhonov
  11. Makhabbat S. Bekbossynova
  12. Natasha S. Barteneva

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Abstract

Coagulation parameters are important determinants for COVID-19 infection. We conducted meta-analysis to assess the association between early hemostatic parameters and infection severity.

Methods

Electronic search was made for papers that addressed clinical characteristics of COVID-19 patients and disease severity. Results were filtered using exclusion and inclusion criteria and then pooled into a meta-analysis to estimate the standardized mean difference (SMD) with 95% confidence interval (CI) for D-dimers, fibrinogen, prothrombin time, platelet count (PLT), activated partial thromboplastin time. To explore the heterogeneity and robustness of our fundings, sensitivity and subgroup analyses were conducted. Publication bias was assessed with contour-enhanced funnel plots and Egger's test by linear regression. Coagulation parameters data from retrospective cohort study of 451 patients with COVID-19 at National Research Center for Cardiac Surgery were included in meta-analysis of published studies.

Results

Overall, 41 original studies (17,601 patients) on SARS-CoV-2 were included. For the two groups of patients, stratified by severity, we identified that D-dimers, fibrinogen, activated partial thromboplastin time, and prothrombin time were significantly higher in the severe group [SMD 0.6985 with 95%CI (0.5155; 0.8815); SMD 0.661 with 95%CI (0.3387; 0.9833); SMD 0.2683 with 95%CI (0.1357; 0.4009); SMD 0.284 with 95%CI (0.1472; 0.4208)]. In contrast, PLT was significantly lower in patients with more severe cases of COVID-19 [SMD −0.1684 with 95%CI (−0.2826; −0.0542)]. Neither the analysis by the leave-one-out method nor the influence diagnostic have identified studies that solely cause significant change in the effect size estimates. Subgroup analysis showed no significant difference between articles originated from different countries but revealed that severity assessment criteria might have influence over estimated effect sizes for platelets and D-dimers. Contour-enhanced funnel plots and the Egger's test for D-dimers and fibrinogen revealed significant asymmetry that might be a sign of publication bias.

Conclusions

The hemostatic laboratory parameters, with exception of platelets, are significantly elevated in patients with severe COVID-19. The two variables with strongest association to disease severity were D-dimers and fibrinogen levels. Future research should aim outside conventional coagulation tests and include analysis of clotting formation and platelet/platelet progenitors characteristics.

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  1. Version published to 10.3389/fcvm.2022.794092
  2. ScreenIT

    SciScore for 10.1101/2021.10.17.21265108: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The study protocol was approved by the medical ethics committee of the National Research Center for Cardiac Surgery, Nur-Sultan, Kazakhstan waiving the need for written informed consent due to the retrospective design.
    Consent: The study protocol was approved by the medical ethics committee of the National Research Center for Cardiac Surgery, Nur-Sultan, Kazakhstan waiving the need for written informed consent due to the retrospective design.
    Sex as a biological variablePapers that focused on pregnant women, children, or specific age groups were avoided.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    2.1 Search Strategy, Exclusion and Inclusion criteria: To broaden our search, we included Ovid, PubMed, Web of Sciences, and Google Scholar in the study.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Google Scholar
    suggested: (Google Scholar, RRID:SCR_008878)
    The confirmation of SARS-CoV-2 infection was done by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay on nose/throat swab or sputum samples using CFX96® Real-Time System (Bio-Rad Laboratories, Inc., USA).
    Bio-Rad Laboratories
    suggested: (Bio-Rad Laboratories, RRID:SCR_008426)
    2.4 Data analysis: 2.4.1 Data transformation: All data analysis was performed in the RStudio 1.4.1717 with R version 4.1.0 (Integrated Development Environment for R. RStudio, PBC, USA).
    RStudio
    suggested: (RStudio, RRID:SCR_000432)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.10.17.21265108 on medRxiv